Vildagliptin SR tablets are used for type-II diabetes. it is used along with metformin by Doctors prescription.

1. FORMULATION AND EVALUATION OF SUSTAINED RELEASE
TABLETS
OF VILDAGLIPTIN
Under the Guidance of
Mr. P.VISHNU M.Pharm.
Assistant Professor
Presented By
CHAITANYA.B B.Pharm.
Department of Pharmaceutics
CMR COLLEGE OF PHARMACY
(Approved by AICTE & PCI and affiliated to JNTU Hyderabad)
6/12/2012

2. SRF’s describes the slow release of a drug substance from a dosage form to
maintain therapeutic response for extended period of time. Time depends on the
dosage form. In oral form it is in hours, and in parenteral’s it is in days and
months. Ex: Aspirin SR, Dextrim SR.
INTRODUCTION
ADVANTAGES:
Decreased local and systemic side effects
Better drug utilization
Improved efficiency in treatment
DISADVANTAGES:
Decreased systemic availability in comparison to immediate-release conventional
dosage forms
Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.
Reduced potential for dosage adjustment of drugs normally administered in varying
strengths.
6/12/2012

3. Drug Selection For Oral Sustained Release Drug Delivery Systems:
Parameter Comment
Elimination half life Preferably between 0.5- 8 h
Elimination rate constant Required for design
Absolute bioavailability Should be 75% or more
Intrinsic absorption rate Must be greater than release rate
Biopharmaceutical parameters for drug selection
6/12/2012
Parameter Preferred value
Molecular weight/ size < 1000
Solubility > 0.1 mg/ml for pH 1 to pH 7.8
Apparent partition
coefficient
High
Absorption mechanism Diffusion
General absorbability From all GI segments
Release Should not be influenced by pH and
enzymes
Pharmacokinetic parameters for drug selection

4. MATRIX TABLETS:
These are the type of controlled drug delivery systems, which release the drug in
continuous manner by both dissolution as well as diffusion controlled mechanisms. To
control the release of the drugs, which are having different solubility properties, the drug
is dispersed in swellable hydrophilic substances, an insoluble matrix of rigid non swellable
hydrophobic materials or plastic materials.
Advantages of matrix systems
•Very easy to fabricate in a wide range of sizes and shapes.
•Suitable for both non-degradable and degradable system.
•No danger of dose dumping in the case of rupture.
Disadvantages of matrix systems
•Not all the drugs can be blended with a given polymeric matrix.
•Water soluble drugs have a tendency to burst from the system.
6/12/2012

5. Drug Release Mechanism from Matrix Systems:
Drug Release from Hydrophilic Colloid Matrices:
The classic description of the events following immersion of a matrix in aqueous media
is as follows:
Surface area (if water soluble) dissolves and gives a ‘burst effect’.
The hydrophilic polymer hydrates and an outer gel layer is formed.
The gel layer becomes a barrier to the uptake of further water and to the transfer of drug
(if soluble) release occurs by diffusion through the gel layer, insoluble drug is released
by erosion followed by dissolution.
Following erosion the new surface becomes hydrated and forms a new gel layer.
Drug Release from Fat Matrices:
The drug embedded into a melt of fats and waxes is released by leaching and
or hydrolysis as well as dissolution of fats under the influence of enzymes and pH chan
-ges in the gastro intestinal tract. Fatty acids are more soluble in an alkaline rather than
acidic medium. Fatty esters are more susceptible to alkali catalyzed hydrolysis than to acid
catalyzed hydrolysis. Polyethylene, ethyl cellulose and glycerine esters of hydrogenated
resins have been added to modify release pattern.
6/12/2012

6. Drug Release from Inert Matrices:
The release of drugs from insoluble matrices has been investigated and four
types of drug matrix systems can be considered:
•Drug molecularly dissolved in the matrix and drug diffusion occurs by a solution-diffusion
mechanism.
•Drug dispersed in the matrix and then, after dissolution of the drug, diffusion occurs via
a solution- diffusion mechanism.
•Drug dissolved in the matrix and diffusion occurs through water- filled pores in the matrix.
•Drug dispersed in the matrix and then, after dissolution, diffusion occurs through water
filled pores
6/12/2012

7. DIABETES MELLITUS
Diabetes mellitus is a metabolic disorder in which the body does not produce or
properly use insulin. It causes disturbances in carbohydrate, protein, lipid metabolism
and complications such as retinopathy, microangiopathy and nephropathy.
It is a group of metabolic disorders characterized by hyperglycemia. These metabolic
disorders include alterations in the carbohydrate, protein and fat metabolisms
associated with absolute or relative deficiencies in insulin secretion or insulin action.
The characteristics symptoms of diabetes are polyurea , polydypsia , polyphagia,
pruritis, unexpected weight loss..etc.
Classification of Diabetes Mellitus:
1. Insulin dependent diabetes mellitus (IDDM)
2. Non Insulin dependent diabetes mellitus (NIDDM)
3. Maturity onset diabetes of youth (MODY)
4. Gestational Diabetes
6/12/2012

8. CLASIFICATION OF ANTI-DIABETIC DRUGS
 Insulin
 Secretagogues
Sulfonyl ureas E.g : Tolbutamide (Orinase), Glipizide (Glucotrol)..
Meglitanides E.g. : Repaglinide ( Prandin)..
 Sensitizers
Biguanides E.g. : Metformin (Glucophage)…
Thiazolidinediones E.g. : Rosiglitazone ( Avavdia)..
 Alpha Glucosidase inhibitor E.g. : Acarbose ( Glucobay)..
 Peptide analogues
I. Incretin mimetics
Glucagon like peptides (GLP) analogs and agonist E.g. Exenatide..
Gastric inhibitory peptide (GIP)analogs
II. DPP-4inhibitots E.g. : Vildagliptin ( Galvus)
III. Amylin analogs E.g. : Pramlinitide
6/12/2012

9. LITERATURE REVIEW
Hindustan Abdul Ahad et al., (2012) reported to prepare the Formulation of Glimepiride SR
Matrix Tablets Using Hibiscus Rosa-Sinensis Leaves Mucilage and Povidone. Various
formulations of Glimepiride tablets were prepared. The tablets were evaluated and the
optimized formulation was tested for accelerated stability studies. The in vitro dissolution
data was fitting to zero order and the release of drug followed Higuchi's release. The stability
studies revealed that the tablets retain their characteristics even after stressed storage
conditions. it was concluded that the dried Hibiscus mucilage and Povidone combination can
be used as an effective matrix forming material for making SR matrix tablets of Glimepiride.
Mohd Azharuddin et al.,(2011) reported to prepare Formulation And Evaluation of CR Matrix
Tablets of Antihypertensive Drug Using Natural And Synthetic Hydrophilic Polymers. Tablets
were prepared by direct compression method using different drug: polymer concentration.
FT-IR and DSC study revealed no chemical interaction between drug and polymers. Pre and
post compression parameters complied with pharmacopoeial limit for the tablets. In-vitro
release studies was performed and the results indicates that matrix tablet (F9) containing
50% w/w blend of natural and synthetic polymer has better CR for a period of 24 hr.6/12/2012

10. DRK.L.Senthilkumar et al.,(2011) reported to prepare the Metformin Hcl tablets by using different
polymers like HPMC K 100M,HPMC K15 with different ratios. Tablets were prepared by wet
granulation technique. Finally It is concluded that formulation of sustained release tablet of
Metformin containing 13 % HPMC K100 with binder PVP K30 as an optimized formulation of
sustained release tablets for 10 hour release as it fulfils all the requirements for sustained release
tablets.
Harsha V. Patel et al., (2009) reported to prepare the sustained release matrix tablets of
Metformin Hcl. The tablets were prepared by the non-aqueous wet granulation method. Isopropy
alcohol solution of polyvinylpyrrolidone (PVPK30) was used as granulating agents along with
hydrophilic matrix materials like hydroxypropyl methylcellulose (HPMC-K15) and locust bean
gum (LBG). The results of dissolution studies indicated that formulation of (HPMC: LBG, 200:30 mg
could extend the drug release up to 8 hours. The successful formulation of the study, exhibited
satisfactory drug release was compared with the marketed formulation (Obimet SR™) and showed
very close to release profile which suggests sustained release profile.
6/12/2012

11. AIM
To prepare and evaluate the Sustained release matrix tablets of an anti diabetic
drug of Vildagliptin(50mg)
OBJECTIVES
•To study the preformulation factors such as melting point, compatibility studies,
etc.
•To formulate a sustained release composition which releases drug over a time
period of about 24 hours.
•To develop a physicochemical stable dosage form.
•To develop a in vitro dissolution profile of all formulations.
•To evaluate the optimized formulation by establishing drug release kinetics using
various dissolution models.
6/12/2012

12. PLAN OF WORK
Selection of the
drug
Selection of excipients
Drug- excipient compatibility by FT-IR
Pre-compression evaluation
compression
Angle of repose
Bulk density
Tapped density
Hausner’ ratio
Carr’s index
Post compression
evaluation
Thickness of Tablet
Hardness
Weight Variation
Friability
Drug Content
Dissolution time
6/12/2012

13. S. No. Name
Category Suppliers of
Material
1
Vildagliptin Hypoglycaemic agent Affine Chemicals
Ltd.
2
MCC IP(Avicel PH
101)
Diluent
Ran Q Remedies
3
HPMC K 100LV Drug release retarding
polymer Dow Chemicals
4
HPMC K 15M Drug release retarding
polymer Dow Chemicals
5
HPMC K 100 M Drug release retarding
polymer Dow Chemicals
6
HPMC K4M Drug release retarding
polymer Dow Chemicals
7 Povidone K 30 Binding agent Basf
8 MCC IP(PH 102) Diluent Ran Q Remedies
9 Talc Glidant Aravelli pvt.Ltd.
10
Magnesium
Stearate
Lubricant Amshi Drug and
Chemicals
11 Water Vehicle
List of materials used
6/12/2012

14. DRUG PROFILE
Chemical name: (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine- 2-carbonitrile
Molecular Formula : C17H25N3O2
Molecular Weight : 303.399
Chemical structure :
6/12/2012

15. Description : A white or slightly yellow colour powder.
Melting Point : 150oC.
Solubility : freely soluble in water and organic solvents.
Therapeutic Category : dipeptidyl peptidase-4(DPP-4),
anti diabetic agent.
Mechanism of Action : Vildagliptin inhibits dipeptidyl peptidase-4 (DPP-4). This in
turn inhibits the inactivation of GLP-1 by DPP-4, allowing GLP-1 to potentiate the
secretion of insulin in the beta cells.
It inhibits the inactivation of GLP-1 and GIP by DPP-4,allowing GLP-1 and
GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon
release by the alpha cells of the islets of Langerhans in the pancreas.
GIP - glucose dependent insulinotropic polypeptide
GLP-1 -glucagon like peptide1
6/12/2012

16. Absorption:
The absolute bioavailability is 85%.
Distribution :
The plasma protein binding of vildagliptin is low (9.3%).
Metabolism:
The major metabolite (LAY 151) is pharmacologically inactive and is the
hydrolysis product of the cyano moiety, accounting for 57% of the dose,
followed by the amide hydrolysis product (4% of dose).
Elimination :
The half-life after i.v administration is - 2 hours.
The half-life after oral administration is -3hours.
Dose: 50-100 mg daily once
6/12/2012

17. LIST OF EQUIPMENTS USED
Compression Machine Cadmach
Electronic Balance
Sartorius
Fluidized Bed Dryer Betochem
Multi Mill Betochem
Vernier Caliper Mitutoyo Corps
Tablet Friability Tester
Labindia-Ft1020
Tablet Hardness Tester
Monsanto type
Karl Fischer Apparatus Labindia
Dissolution Test Apparatus Labindia-Ds 8000
Uv-Visible Spectrophotometer Labindia-Uv 3200 Double
Beam Spectrophotometer
6/12/2012

18. S.No Properties Description
1. Color White to slightly yellowish crystalline powder
2. Odor Characteristic
3. Taste Metallic
Organoleptic characteristics
4. Melting point 150⁰C
PRE FORMULATION STUDIES
6/12/2012

19. Drug- excipient compatibility studies by FT-IR:
2mg drug+ 200mg KBr
Mix well
Pellet preparation
Sample cell
spectra were recorded over the wave number of 4000 to 400cm-1.
6/12/2012

20. Drug-Excipient compatibility studies by FT-IR
Drug-Excipient compatibility studies by FT-IR
6/12/2012

21. MANUFACTURING PROCEDURE:
Weigh accurate amounts of Vildagliptin+pH101+polymers HPMC(K15M,K100M,K4M& K100LV)
mix for 5 min and sieved through 40 mesh
preparation of binding solution(PVP K-30+water)
preparation of wet mass(binding solution +mixed ingredients)
sieved through 16 mesh
Dry the wet granules at 60⁰C until LOD is 1-3 % w/w
add pH102 to the granules
dried granules were mixed with talc, magnesium stearate (sieved through 60 mesh)
finally compress the tablet.
6/12/2012

22. INGREDIENTS
(mg/tab)
F1 F2 F3 F4 F5 F6 F7 F8
Vildagliptin 50 50 50 50 50 50 50 50
MCCpH101 130 130 130 130 130 130 130 ―
HPMC K 100LV ― ― ― 120 ― ― 50 148
HPMC K 15M ― 120 ― ― 50 ― ― 100
HPMC K 100 M ― ― 120 ― ― 50 ― ―
HPMC K4M 120 ― ― ― 90 90 90 32
Povidone K 30 12 12 12 12 12 12 12 12
MCCpH 102 20 20 20 20 20 20 20 20
Talc 4 4 4 4 4 4 4 4
Magnesium
Stearate
4 4 4 4 4 4 4 4
Water q.s q.s q.s q.s q.s q.s q.s q.s
340 340 340 340 360 360 360 370
Formulations of Vildagliptin matrix tablets (50mg tablet)
Total wt (mg)
6/12/2012

23. 6/12/2012
PRE COMPRESSION PARAMETERS
Angle of repose
Bulk density
Tapped density
Compressibility index
Hausner’s ratio

24. S.
No
Formulatio
n code
Bulk
Density
(g/ml)
Tapped
Density
(g/ml)
Compressi
bility Index
(%)
Hausner’s
Ratio
Angle of
repose
(⁰)
1 F-1 0.48±0.02 0.625±0.1 21.23±0.21 1.32±0.14 38.5±0.23
2 F-2 0.583±0.15 0.745±0.21 23.60±0.16 1.27±0.05 38.5±0.15
3 F-3 0.490±0.12 0.635±0.31 22.45±0.31 1.33±0.08 37.2±0.26
4 F-4 0.581±0.01 0.714±0.14 16.67±0.25 1.2±0.16 36.5±0.09
5 F-5 0.654±0.21 0.802±0.26 15.07±0.31 1.19±0.21 35.4 ±0.21
6 F-6 0.694±0.09 0.834±0.09 16.09±0.16 1.21±0.18 34.5±0.19
7 F-7 0.510±0.06 0.641±0.28 17.74±0.17 1.22±0.22 35±0.17
8 F-8 0.582±0.01 0.714±0.13 12.45±0.13 1.15±0.24 32.5±0.14
Pre compression parameters
6/12/2012

25. 6/12/2012
Compression parameters
Description White, Round biconvex tablets
debossed with R on one side
and F8 on other side
Tooling 13.10*6.50 mm,Round shape
biconcave punches
Weight of 10 tablets (g) 3.7
Weight of individual tablet (mg) 370.000 5% (340.00-370.000)
Hardness(k p) NLT 3 (6-7)
Thickness (mm) 5.50 0.2 (5.48-5.52)
Friability % NMT 1%

26. 6/12/2012
Post compression parameters:
 Thickness of Tablet
 Weight variation test
 Hardness
 Friability
 Water content
 Assay
 Dissolution studies

27. Batch
code
Weight
Variation(mg)
n=20
Thickness
(mm)
n=10
Hardness
(Kg/cm²)
n=5
Friability
(%w/w)
n=10
Assay(%)
n=5
Water
content(%)
F1 340±3.01 5.52±0.2 6.5±0.02 0.15±0.01 96.5±0.9 6.39±0.01
F2 340±2.89 5.48±0.2 7.0±0.2 0.18±0.01 96.0±1.8
6.35±0.21
F3 340±3.05 5.5±0.2 6.5±0.2 0.21±0.01 95.5±1.5
6.45±0.15
F4 340±2.98 5.52±0.2 6.8±0.2 0.19±0.01 105±2.1
6.58±0.21
F5 360±3.00 5.48±0.2 6.9±0.02 0.34±0.01 97.5±1.4
6.15±0.18
F6 360±2.95 5.52±0.2 6.9±0.2 0.19±0.02 96±0.9 6.38±0.24
F7 360±2.99 5.48±0.2 7.0±0.01 0.22±0.01 98±0.51 6.55±0.09
F8 370±2.97 5.52±0.2 7.1±0.2 0.21±0.01 99.8±0.84 6.13±0.16
Physical properties of sustained release matrix tablets of vildagliptin
6/12/2012

28. The λmax of vildagliptin was 245 nm.
6/12/2012

29. Calibration curve with pH 6.8 phosphate buffer
S.No Concentration
(μg/ml)
Absorbance
1. 0 0
2. 2 0.189
3. 4 0.375
4. 6 0.539
5. 8 0.756
6. 10 0.923
Results of calibration curve
R² = 0.999
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 5 10 15
absorbance
concentration(μg/ml)
6/12/2012

30. Apparatus USP type II (Paddle)
Type of medium Phosphate buffer pH 6.8
Sampling
time intervals(hr)
1, 4, 8, 12, 16, 20 & 24
λmax 245nm
In-vitro Dissolution studies:
Bowl Temperature - 37 C
Bath Temperature - 40 C
Stir speed - 50 rpm
6/12/2012

31. S.No Time
(hr)
F1 F2 F3 F4 F5 F6 F7 F8
1. 1 5.6±0.5 6.7±0.4 3.5±0.3 30.5±1 5.8±0.4 4.9±0.4 5.5±0.5 6.9±0.5
2. 4 32.2±1.3 28±1.1 19.9±0.8 65.1±1.2 30.1±1.4 23.9±1.1 30.7±1.4 28.4±1.1
3. 8 46.3±1.6 36.6±1.5 35.2±1.8 86.9±1.9 38.4±1.1 31.5±0.7 52.5±1.2 44.6±1.5
4. 12 55.2±0.8 49.6±1.9 42.4±1.3 95.4±0.6 49.3±1.1 38.9±1.2 69.1±1.8 58.9±1.1
5. 16 72.4±0.5 58±0.7 46.7±1.5 99±1.1 57±1 43.6±1.5 81.5±0.8 72.9±0.9
6. 20 80.8±2 67.2±0.8 50.1±1 - 66.7±1.9 57.5±0.8 99.4±0.8 87.5±0.6
7. 24 85.3±1.3 73.2±2.3 55.6±1.3 - 71.1±0.4 62.2±1.3 - 98.6±1
Cumulative percentage drug release profile of all formulations
6/12/2012
n=3 , ±=S.D

32. Graphs of Cumulative percentage drug release
of all formulations
6/12/2012
0
10
20
30
40
50
60
70
80
90
0 5 10 15 20 25 30
%CDR
Time(hrs)
Cumulativedrug releaseof F1,F2,F3
F1
F2
F3

33. Order of drug release:
Zero order
First order
R² = 0.985
0
20
40
60
80
100
120
0 10 20 30
%OFDRUGRELEASE
TIME(Hr)
R² = 0.815
0
0.5
1
1.5
2
2.5
0 10 20 30
Log%DRUGREMAIN
TIME(Hr)
6/12/2012

34. Mechanism of drug release:
Higuchi Plot of Diffusion Kinetics :
R² = 0.994
0
20
40
60
80
100
120
0 2 4 6
DRUGRELEASE%
SQUARE ROOT OF TIME(Hr)
R² = 0.990
0
0.5
1
1.5
2
2.5
0 0.5 1 1.5
LOG%CDR
LOG TIME (Hr)
R² = 0.873
0
1
2
3
4
5
6
0 10 20 30
CUBEROOTOF
%DRUGRELEASE
TIME(Hr)
Korsemeyer peppas Diffusion kinetics
Hixon-crowell Diffusion kinetics
6/12/2012

35. SUMMARY
•Eight formulations were developed by different grades of HPMC (K100 LV, K15M,K4M
and K100M) by wet granulation technique.
•The preformulation studies like organoleptic properties, melting point were carried out.
•The drug-excipients compatibility studies were conducted by using FTIR, there was no
interaction between drug and excipients.
•The calibration curve was prepared in pH 6.8 phosphate buffer, the λmax was found to
be 245nm.
•The developed formulations were evaluated for various pre-compression and post-
compression parameters.
•The invitro dissolution profile was conducted to all formulations.
•Among all formulations,F8 was found to be the most suitable sustained release
formulation.
•The best linearity was found in zero order release and mechanism of release was
fitted to Higuchi diffusion.
6/12/2012

36. CONCLUSION
Vildagliptin is used for the treatment and relief of diabetes mellitus-type II.
Drug release from the matrix was found to depend on the combination of
polymer concentration, where as the polymer concentration was employed from
20-50%w/w of the average tablet weight.
HPMC K100LV, HPMC K15M, HPMC K4M required to channelize the drug release
was optimized to 95 to 99%.
In conclusion, a stable sustained release matrix tablet formulation of
Vildagliptin was successfully developed and in vitro drug release pattern
up to 24 hours.
6/12/2012

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39. 6/12/2012
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